1,3-dihydro-2H-imidazol-2-one compounds

ABSTRACT

The present invention concerns the compounds of formula ##STR1## the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein R 1  and R 2  each independently are hydrogen; C 1-6  alkyl; difluoromethyl; trifluoromethyl; C 3-6  cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo 2.2.1!-2-heptenyl; bicyclo 2.2.1!heptanyl; C 1-6  alkylsulfonyl; arylsulfonyl; or substituted C 1-10  alkyl; R3 is hydrogen, halo or C 1-6  alkyloxy ##STR2## is a bivalent radical of formula ##STR3## Alk is C1-4alkanediyl; --A--B-- is a bivalent radical of formula: --CR 6  ═CR 7  -- or --CHR 6  --CHR 7  --; L is hydrogen; optionally substituted C 1-6  alkyl; C 1-6  alkylcarbonyl; C 1-6  alkyloxycarbonyl; optionally substituted C 3-6  alkenyl; optionally substituted piperidinyl; C 1-6  alkylsulfonyl or arylsulfonyl; aryl is optionally substituted phenyl; Het 1  is morpholinyl or optionally substituted pyridinyl, -furanyl, -thienyl, -hydroxypyridinyl, -imidazolyl, -thiazolyl, -oxazolyl, -isoquinolinyl, -quinolinonyl, -piperidinyl, -piperazinyl; and Het 2  is morpholinyl or optionally substituted piperidinyl, -piperazinyl, -pyridinyl, -furanyl or -thienyl; having PDE IV and cytokine inhibiting activity. The invention also relates to processes for preparing the compounds of formula (I) and pharmaceutical compositions thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT application Ser. No. PCT/EP96/01393,filed Mar. 28, 1996, which claims priority from European PatentApplication Serial No. 95.200.870.4, filed on Apr. 6, 1995.

The present invention concerns 1,3-dihydro-2H-imidazol-2-one derivativeshaving PDE IV and cytokine inhibiting activity and their preparation; itfurther relates to compositions comprising them, as well as their use asa medicine.

WO 94/12461 generically discloses a number of1-(benzoylalkyl)-2-hydroxy-imidazole derivatives as selective inhibitorsof phosphodiesterase type IV (PDE IV).

Unexpectedly, particular 1,3-dihydro-2H-imidazol-2-one derivatives showimproved PDE IV inhibiting activity over the art compounds. In addition,the compounds of the present invention were found to display cytokineinhibiting activity. In view of these pharmacological properties, thepresent compounds have therapeutical utility in the treatment of diseasestates related to an abnormal enzymatic or catalytic activity of PDE IV,and/or disease states related to a physiologically detrimental excess ofcytokines, in particular allergic, atopic and inflammatory diseases.

The present invention concerns 1,3-dihydro-2H-imidazol-2-one derivativeshaving the formula ##STR4## the N-oxide forms, the pharmaceuticallyacceptable acid or base addition salts and the stereochemically isomericforms thereof, wherein: R¹ and R² each independently are hydrogen; C₁₋₆alkyl; difluoromethyl; trifluoromethyl; C₃₋₆ cycloalkyl; a saturated 5-,6- or 7-membered heterocycle containing one or two heteroatoms selectedfrom oxygen, sulfur or nitrogen; indanyl; bicyclo 2.2.1!-2-heptenyl;bicyclo 2.2.1!heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen;

R³ is hydrogen, halo or C₁₋₆ alkyloxy; ##STR5## is a bivalent radical offormula ##STR6## wherein: R⁴ is hydrogen; cyano; C₁₋₆ alkyl; C₁₋₄alkyloxycarbonyl; C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;

R⁵ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy,carboxyl, C₁₋₄ alkyloxycarbonyl, amino, aminocarbonyl, mono- or di(C₁₋₄alkyl)amino, mono- or di(C₁₋₄ alkyl)aminocarbonyl, Het¹ or aryl;

n is 1, 2, 3, 4 or 5;

Alk is C₁₋₄ alkanediyl;

--A--B-- is a bivalent radical of formula: ##STR7## wherein each R⁶ andR⁷ independently is hydrogen or C₁₋₄ alkyl;

L is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆ alkyloxycarbonyl;C₁₋₆ alkyl substituted with one or two substituents selected from thegroup consisting of hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, mono-and di(C₁₋₄ alkyl)amino, aryl and Het² ; C₃₋₆ alkenyl, C₃₋₆ alkenylsubstituted with aryl; piperidinyl: piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; C₁₋₆ alkylsulfonyl or arylsulfonyl;

aryl is phenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl,trifluoromethyl, amino, nitro, carboxyl, C₁₋₄ alkyloxycarbonyl and C₁₋₄alkylcarbonylamino;

Het¹ is pyridinyl; pyridinyl substituted with C₁₋₄ alkyl; furanyl;furanyl substituted with C₁₋₄ alkyl; thienyl; thienyl substituted withC₁₋₄ alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substitutedwith C₁₋₄ alkyl or C₁₋₄ alkoxyC₁₋₄ alkyl; imidazolyl; imidazolylsubstituted with C₁₋₄ alkyl; thiazolyl; thiazolyl substituted with C₁₋₄alkyl; oxazolyl; oxazolyl substituted with C₁₋₄ alkyl; isoquinolinyl;isoquinolinyl substituted with C₁₋₄ alkyl; quinolinonyl, quinolinonylsubstituted with C₁₋₄ alkyl; morpholinyl; piperidinyl; piperidinylsubstituted with C₁₋₄ alkyl, C₁₋₄ alkyloxycarbonyl or arylC₁₋₄ alkyl;piperazinyl; piperazinyl substituted with C₁₋₄ alkyl, C₁₋₄alkyloxycarbonyl or arylC₁₋₄ alkyl; and

Het² is morpholinyl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; piperazinyl; piperazinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; pyridinyl; pyridinyl substituted with C₁₋₄alkyl; furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl or thienylsubstituted with C₁₋₄ alkyl or C₁₋₄ alkylcarbonylamino.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

In R¹ and R², the saturated 5-, 6- or 7-membered heterocycles containingone or two heteroatoms selected from oxygen, sulfur or nitrogen maysuitably be selected from heterocycles such as, for example,tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl and tetrahydropyranyl. Said heterocyclic radicals areattached to the C₁₋₁₀ alkyl radical by any carbon atom or, whereappropriate, by a nitrogen atom.

As used in the foregoing definitions the term halo is generic to fluoro,chloro, bromo and iodo; the term C₁₋₄ alkyl is meant to include straightchained or branched saturated hydrocarbons having from 1 to 4 carbonatoms such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 2-methylpropyl and butyl; the term C₁₋₆ alkylis meant to include C₁₋₄ alkyl and the higher homologues thereof having5 or 6 carbon atoms such as, for example, 2-methylbutyl, pentyl, hexyland the like; the term C₃₋₆ alkenyl defines straight and branch chainedhydrocarbon radicals containing one double bond and having from 3 to 6carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl,2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbonatom of said C₃₋₆ alkenyl being connected to a nitrogen atom preferablyis saturated; the term C₃₋₆ cycloalkyl is generic to cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl; the term C₁₋₄ alkanediyl ismeant to include straight chained and branched saturated bivalenthydrocarbon radicals having 1 to 4 carbon atoms, such as, for example,methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,2-methyl-1,3- propanediyl and the like.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the acid addition salt forms which canconveniently be obtained by treating the base form of the compounds offormula (I) with appropriate acids such as inorganic acids, for example,hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric,phosphoric and the like acids; or organic acids, such as, for example,acetic, hydroxy-acetic, propanoic, lactic, pyruvic, oxalic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. Conversely, said acidaddition salt forms can be converted in the free base forms by treatmentwith an appropriate base.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

The term "stereochemically isomeric forms" as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration.Compounds of formula (I) wherein >C═X is a bivalent radical of formula(a-2) or (a-3), may occur as mixtures of E- and Z-forms, or as pureE-forms or pure Z-forms.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure steroochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically. The pure and mixed stereochemicallyisomeric forms of the compounds of formula (I) are intended to beembraced within the scope of the present invention.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Whenever used hereinafter, the term compounds of formula (I) is meant toinclude also the N-oxide forms, the pharmaceutically acceptable acid orbase additions salts and all stereoisomeric forms.

A first set of particular groups of compounds of formula (I) consists ofthose wherein one or more of the following provisions apply:

a) R¹ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl and R² is C₁₋₆ alkyl;

b) R³ is hydrogen;

c) Alk is methylene or 1,2-ethanediyl;

d) L is hydrogen or C₁₋₆ alkyl, preferably L is hydrogen;

e) --A--B-- is a bivalent radical of formula (b-1), preferably abivalent radical of formula (b-1) wherein R⁶ and R⁷ are both hydrogen.

A second set of particular groups of compounds of formula (I) consistsof those wherein one or more of the following provisions apply:

1) R¹ is hydrogen; a saturated 5-, 6- or 7-membered heterocyclecontaining one or two heteroatoms selected from oxygen, sulfur ornitrogen; bicyclo 2.2.1!-2-heptenyl; C₁₋₆ alkylsulfonyl; arylsulfonyl;or C₁₋₁₀ alkyl substituted with one or two substituents eachindependently selected from pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyland a saturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen;

2) R² is hydrogen, C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen; indanyl; bicyclo 2.2.1!-2-heptenyl; bicyclo2.2.1!heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen;

3) R³ is halo or C₁₋₆ alkyloxy;

4) ##STR8## is a radical of formula (a-2), (a-3) or (a-4); 5) --A--B--is a bivalent radical of formula (a-2);

6) L is C₁₋₆ alkylcarbonyl; C₁₋₆ alkyl substituted with hydroxy or C₁₋₄alkyloxy; C₃₋₆ alkenyl; C₃₋₆ alkenyl substituted with aryl; C₁₋₆alkylsulfonyl or arylsulfonyl.

An interesting subgroup within said second set of groups consists ofthose compounds of formula (I) wherein ##STR9## is a radical of formula(a-2), (a-3) or (a-4).

Another interesting subgroup within said second set of groups consistsof those compounds of formula (I) wherein R¹ is hydrogen; a saturated5-, 6 - or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen; bicyclo 2.2.1!-2-heptenyl;C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkyl substituted with one ortwo substituents each independently selected from pyridinyl, thienyl,furanyl, C₃₋₇ cycloalkyl and a saturated 5-, 6- or 7-memberedheterocycle containing one or two heteroatoms selected from oxygen,sulfur or nitrogen.

Still another interesting subgroup within said second set of groupsconsists of those compounds of formula (I) wherein R² is hydrogen, C₃₋₆cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing oneor two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl;bicyclo 2.2.1!-2-heptenyl; bicyclo 2.2.1!heptanyl; C₁₋₆ alkylsulfonyl;arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituentseach independently selected from aryl, pyridinyl, thienyl, furanyl, C₃₋₇cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containingone or two heteroatoms selected from oxygen, sulfur or nitrogen.

Preferred compounds are those compounds of formula (I) wherein R¹ isC₁₋₆ alkyl, C₃₋₆ cycloalkyl or C₁₋₁₀ alkyl substituted with C₃₋₇cycloalkyl; R² is C₁₋₆ alkyl; and ##STR10## is a bivalent radical offormula (a-1), (a-2) or (a-3).

Most preferred are the compounds 1- 2-3-(cyclopentyloxy)-4-methoxyphenyl!-2-oxoethyl!-1,3-dihydro-2H-imidazol-2-one;1- 2-3-(cyclopentyloxy)-4-methoxy-phenyl!-2-propenyl!-1,3-dihydro-2H-imidazol-2-one;their pharmaceutically acceptable acid or base addition salts and theirstereoisomeric forms.

Whenever used hereinafter, R¹ to R⁷, ##STR11## Alk, --A--B-- and L aredefined as under formula (I) unless otherwise indicated.

The compounds of formula (I) can generally be prepared by N-alkylating a1,3-dihydro-2H-imidazol-2-one derivative of formula (II) with anappropriately substituted alkylating agent of formula (III), wherein W¹is a reactive leaving group such as, for example, a halogen. ##STR12##Said N-alkylation may conveniently be performed in the presence of abase such as, for example, sodium hydride, butyllithium or sodiumbis(trimethylsilyl)amide, in a reaction-inert solvent such as, forexample, tetrahydrofuran, optionally cooled on an ice-bath. The reactionis preferably performed under a reaction inert atmosphere such as, forexample, oxygen free nitrogen. It may be advantageous to add to thereaction mixture a crown ether, e.g.1,4,7,10,13,16-hexaoxacyclooctadecane and the like or a complexing agentsuch as for example, tris 2-(2-methoxyethoxy)!ethanamine and the like.Stirring may enhance the rate of the reaction. In case intermediates offormula (II), wherein L is replaced by a suitable protecting group, areused in said N-alkylation reaction, compounds of formula (I) wherein Lis hydrogen, said compounds being represented by compounds of formula(I-a), may be obtained using art-known deprotection reactions.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

Alternatively, compounds of formula (I) may be prepared by reacting anorganometallic intermediate of formula (IV), wherein M is an appropriatemetal ion or metalcomplex ion such as, for example, Li⁺, (MgBr)⁺, B(OH)₂⁺ or Sn(CH₃)₃ ⁺, with a suitable 1,3-dihydro-2H-imidazol-2-onederivative of formula (V) wherein W² is a reactive leaving group suchas, for example, a halogen or a substituted amine. ##STR13## Saidreaction may be performed in a reaction-inert solvent such as, forexample, dimethoxyethane, tetrahydrofuran or diethylether. Stirring andheating may enhance the rate of the reaction. In case intermediates offormula (V), wherein L is replaced by a suitable protecting group, areused in said reaction, compounds of formula (I) wherein L is hydrogen,said compounds being represented by compounds of formula (I-a), may beobtained using art-known deprotection reactions.

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional group transformation.

In particular, compounds of formula (I) wherein L is other thanhydrogen, said compounds being represented by formula (I-b), may beprepared by reacting a compound of formula (I-a) with L'-W³ (VI) whereinL' is the same as L but other than hydrogen, and W³ is a reactiveleaving group such as, for example, a halogen atom. ##STR14## Alsoart-known addition reactions may be used to convert compounds of formula(I-a) into compounds of formula (I-b).

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or earth alkaline metalperoxides, e.g. sodium peroxide, potassium peroxide; appropriate organicperoxides may comprise peroxy acids such as, for example,benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide.Suitable solvents are, for example, water, lower alkanols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Compounds of formula (I) wherein ##STR15## is a radical of formula(a-1), said compounds being represented by (I-1) may be prepared byoxidation of an intermediate of formula (VII) with a suitable oxidizingagent such as, for example, oxalyl chloride, in the presence of anappropriate base such as, for example, triethylamine, and in areaction-inert solvent such as, for example, dichloromethane. Thereaction is conveniently carried at low temperatures, for instance -60°C., and under an oxygen free atmosphere, for instance, a N₂ atmosphere.##STR16## Compounds of formula (I-1) may further be reacted with aWittig reagent of formula (VIII) wherein Y is a suitable counter ionsuch as, for example, a halogen, thus forming a compound of formula (I)wherein <C═x is a radical (a-2), said compounds being represented byformula (I-2). Said reaction may be performed in a reaction-inertsolvent in the presence of a base such as, for example, butyllithium orsodium hydride. The phosphonium salt-type intermediates of formula(VIII) may conveniently be replaced by the corresponding more reactivephosphonic ester-type intermediates of formula (VIII). ##STR17##Compounds of formula (I) wherein ##STR18## is a radical of formula (a-3)and R⁵ is hydrogen, said compounds being represented by formula (I-3-1),may be prepared by reacting a compound of formula (I-1) withhydroxylamine or a functional derivative thereof, in a reaction-inertsolvent such as, for example, ethanol or pyridine, and optionally in thepresence of a base such as, for example, sodium carbonate ordiethylethanamine. The thus obtained oxime of formula (I-3-1) may bereacted with R⁵ '-W⁴ (IX) wherein W⁴ is a reactive leaving group suchas, for example, a halogen atom, and R⁵ ' is the same as R⁵ but otherthan hydrogen, thus obtaining a compound of formula (I-3-2). ##STR19##The reagents and intermediates of formula (II), (III), (IV), (V), (VI),(VIII) and (IX) required for the synthesis of the compounds of thepresent invention are either commercially readily available, or may beprepared according to known procedures.

Intermediates of formula (VII) wherein L is hydrogen and Alk ismethylene, said intermediates being represented by formula (VII-a), maybe prepared following the reaction process as depicted in scheme 1.##STR20## Step i) in scheme 1 involes the reaction of an intermediate offormula (X) with trimethylsilyl cyanide or a functional derivativethereof in the presence of a suitable catalyst such as, for example,zinc iodide, and in a reaction-inert solvent such as, for example,dichloromethane; thus forming an intermediate of formula (XI) wherein Pis a trimethylsilyl protecting group or a functional derivative thereof.Depending on the nature of the R¹, R² and R³ variables, P may also behydrogen. Subsequently, in step ii), the nitrile derivative of formula(XI) may be reduced to the corresponding amine of formula (XII) usingart-known techniques such as, for example, reduction with hydrogen inthe presence of a suitable catalyst such as, for example, Raney nickel.Further, in step iii), an intermediate of formula (XII) may be reactedwith an imidazole derivative of formula (XIII) in a reaction-inertsolvent such as, for example, tetrahydrofuran, preferably a temperatureranging between room temperature and reflux temperature; thus forming anintermediate of formula (XIV). Finally, step iv) involes the cyclizationof an intermediate of formula (XIV) to an intermediate of formula(VII-a) in the presence of a suitable acid such as, for example,hydrochloric acid.

The compounds of formula (I), the N-oxide forms, pharmaceuticallyacceptable acid or base addition salts and the stereochemically isomericforms thereof, are potent inhibitors of the phosphodiesterase (PDE)isoenzymes of family IV (cAMP-specific family).

cAMP (adenosine cyclic 3',5'-monophosphate) is a key second messenger,the concentration of which affects particular cell activities throughactivation of enzymes such as kinases. PDE IV is known to hydrolyse cAMPto its corresponding inactive 5'-monophosphate metabolite. Hence,inhibition of PDE IV leads to an elevation of cAMP levels in particularcells such as the respiratory smooth muscle cell and in a wide varietyof inflammatory cells, i.e. certain lymphocytes, e.g. basophils,neutrophils and eosinophils, monocytes and mast-cells. A number ofallergic, atopic and inflammatory diseases are deemed to be caused byhigher-than-normal PDE IV concentrations which result in low cAMP levelsand hypersensitivity of the thus affected cells for excitatory stimuli.(Examples of said hypersensitivity are for example, excessive histaminerelease from basophils and mast cells or excessive superoxide anionradical formation by eosinophils.) Hence, the present compounds havingpotent phosphodiesterase IV inhibitory properties are deemed usefulagents in alleviating and/or curing allergic, atopic and inflammatorydiseases. The functional effects of PDE IV inhibitors are e.g.respiratory smooth muscle relaxation, bronchodilation, plateletaggregation inhibition and inhibition of white blood cell mediatorrelease. Examples of allergic diseases are bronchial asthma, cheilitis,conjunctivitis, contact dermatitis and eczema, irritable bowel disease,deshydroform eczema, urticaria, vasculitis, vulvitis; examples of atopicdiseases are dermatitis and eczema, winterfeet, asthma, allergicrhinitis; and related afflictions are, for example, psoriasis and otherhyperproliferative diseases.

The present invention thus also relates to compounds of formula (I) asdefined hereinabove for use as a medicine, in particular for use as ananti-asthmatic medicine or as a medicine for treating atopic diseases.Thus the compounds of the present invention may be used for themanufacture of a medicament for treating asthmatic or atopic diseases,more in particular atopic dermatitis.

The PDE IV inhibitory activity of the compounds of formula (I) may bedemonstrated in the test "Inhibition of recombinant human mononuclearlymphocyte (MNL) phosphodiesterase type IV B produced in insect cellswith a baculovirus vector". Several in vivo and in vitro tests may beused to demonstrate the usefulness of the compounds of formula (I) intreating the described allergic, atopic and inflammatory diseases. Suchtests are for instance, "Bronchoconstriction of the guinea pig tracheain vitro", "Bronchoconstriction of the guinea pig trachea in vivo" andthe in vivo test "Dextran-induced oedema formation in mouse ear".

Further, the present compounds have only very low inhibitory activity onthe phosphodiesterase isoenzymes of family III (cGMP-inhibited family).Inhibition of, in particular, PDE III leads to an elevation of cAMP inthe cardiac muscle, thereby causing effects on the contractile force ofthe heart as well as on the relaxation of the heart. In the treatment ofthe described allergic, atopic and inflammatory diseases, cardiovasculareffects clearly are undesired. Hence, as the present compounds inhibitPDE IV at much lower concentrations as they inhibit PDE III, theirtherapeutic use may be adjusted to avoid cardiovascular side-effects.

Art-known PDE IV inhibitors often cause adverse gastro-intestinal sideeffects. Most of the present compounds, however, have few effects on thegastro-intestinal tract, which may be demonstrated in the test "Gastricemptying of a caloric meal in rats".

The designation PDE III and IV as used herein refers to theclassification by J. A. Beavo and D. H. Reifsnyder, TIPS Reviews, April1990, pp. 150-155.

The compounds of the present invention also have cytokine inhibitoryactivity. A cytokine is any secreted polypeptide that affects thefunction of other cells by modulating interactions between cells in theimmune or inflammatory response. Examples of cytokines are monokines andlymphokines and they may be produced by a wide variety of cells. Forinstance, a monokine is generally referred to as being produced andsecreted by a mononuclear cell, such as a macrophage and/or monocyte butmany other cells produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes, andβ-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include Interleukin-1 (I-1),Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-8 (IL-8),alpha-Tumor Necrosis Factor (αTNF) and beta-Tumor Necrosis Factor(βTNF).

The cytokine specifically desired to be inhibited is αTNF. Excessive orunregulated TNF production is implicated in mediating or exacerbating anumber of diseases including rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis, and other arthriticconditions; sepsis, septic shock, endotoxic shock, gram negative sepsis,toxic shock syndrome, adult respiratory distress syndrome, cerebralmalaria, chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoidosis, bone resorption diseases, reperfusion injury, graft versushost reaction, allograft rejections, fever and myalgias due toinfection, such as influenza, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissueformation, Crohn's disease, ulcerative colitis, or pyresis.

The cytokine inhibitory activity of the compounds of formula (I), suchas the inhibition of αTNF production, may be demonstrated in the invitro test "Cytokine production in human whole blood cultures".

In addition, the compounds of the present invention are expected to showno or little endocrinological side-effects. This may be evidenced by,for instance, the "Testosterone in vivo" test, the "In vitro inhibitionof the aromatase activity"-test and the "In vivo inhibition of thearomatase activity"-test.

In view of their useful PDE IV and cytokine inhibiting properties, thesubject compounds may be formulated into various pharmaceutical formsfor administration purposes. To prepare the pharmaceutical compositionsof this invention, an effective amount of the particular compound, inbase or acid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, which maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, foradministration orally, rectally, topically, percutaneously, byinhalation or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions: or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wettable agent, optionally combined withsuitable additives of any nature in minor proportions, which additivesdo not cause any significant deleterious effects on the skin. Saidadditives may facilitate the administration to the skin and/or may behelpful for preparing the desired compositions. These compositions maybe administered in various ways, e.g., as a transdermal patch, as aspot-on or as an ointment. As appropriate compositions for topicalapplication there may be cited all compositions usually employed fortopically administering drugs e.g. creams, gellies, dressings, shampoos,tinctures, pastes, ointments, salves, powders and the like. Applicationof said compositions may be by aerosol, e.g. with a propellent such asnitrogen, carbon dioxide, a freon, or without a propellent such as apump spray, drops, lotions, or a semisolid such as a thickenedcomposition which can be applied by a swab. In particular, semisolidcompositions such as salves, creams, gellies, ointments and the likewill conveniently be used.

In order to enhance the solubility and/or the stability of the compoundsof formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin. Also co-solvents such as alcohols mayimprove the solubility and/or the stability of the compounds of formula(I) in pharmaceutical compositions. In the preparation of aqueouscompositions, addition salts of the subject compounds are obviously moresuitable due to their increased water solubility.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage.

Dosage unit form refers to physically discrete units suitable as unitarydosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions and the like, and segregated multiples thereof.

The present invention also relates to a method of treating warm-bloodedanimals suffering from disease states related to an abnormal enzymaticor catalytic activity of PDE IV, and/or disease states related to aphysiologically detrimental excess of cytokines, in particular allergic,atopic and inflammatory diseases, more in particular asthmatic andatopic diseases, most particular atopic dermatitis. Said methodcomprises the administration of a therapeutically effective amount of acompound of formula (I) or a N-oxide form, a pharmaceutically acceptableacid or base addition salt or a stereochemically isomeric form thereofin admixture with a pharmaceutical carrier.

In general it is contemplated that an effective daily amount would befrom 0.01 mg/kg to 10 mg/kg body weight, more preferably from 0.04 mg/kgto 5 mg/kg body weight. It is evident that said effective daily amountmay be lowered or increased depending on the response of the treatedsubject and/or depending on the evaluation of the physician prescribingthe compounds of the instant invention. The effective daily amountranges mentioned hereinabove are therefore guidelines only and are notintended to limit the scope or use of the invention to any extent.

The following examples are intended to illustrate and not to limit thescope of the present invention.

EXPERIMENTAL PART

Compounds of formula (I) and some intermediates have a stereogeniccenter. In those cases where the racemate was separated into itsenantiomers, the stereochemically isomeric form which was first isolatedwas designated as "A" and the second as "B", without further referenceto the actual stereochemical configuration.

Hereinafter, "THF" means tetrahydrofuran and "RT" means roomtemperature.

A. PREPARATION OF THE INTERMEDIATES EXAMPLE A.1

Under a N₂ flow, a solution of benzyltrimethylammonium dichloroiodate(78 g) in THF (250 ml) was added to a mixture of 1-3-(cyclopentyloxy)-4-methoxyphenyl!ethanone (26.3 g) in THF (250 ml)while stirring. The resulting reaction mixture was stirred for 16 hoursat RT. The solvent was evaporated and the residue was redissolved indiethyl ether (300 ml). The mixture was added dropwise to a 5% Na₂ S₂ O₄solution (400 ml). The aqueous layer was extracted twice with diethylether (2×100 ml). The combined organic layers were washed with water(2×500 ml), dried over MgSO₄, filtered and the solvent evaporated. Thecrude oil was crystallized from hexane. The precipitate was filteredoff, washed with hexane and dried, yielding 11 g of 2-chloro-1-3-(cyclopentyloxy)-4-methoxyphenyl!ethanone. The filtrate was evaporatedand the residue was crystallized from hexane. The precipitate wasfiltered off and dried, yielding 7.4 g (24.6%) of 2-chloro-1-3-(cyclopentyloxy)-4-methoxyphenyl!ethanone (interm. 1).

EXAMPLE A.2

a) A solution of 4-methoxybenzenemethanamine (72.7 g) and triethylamine(83.6 ml) in CH₂ Cl₂ (750 ml) was cooled on an ice-bath.Phenylchloroformate (91.4 g) was added dropwise and the reaction mixturewas stirred at RT. The reaction mixture was washed three times withwater and the precipitate was filtered off. The organic layer wasseparated, washed three times with a 5% aqueous NaHCO₃ solution, dried(MgSO₄), filtered and the solvent was evaporated. The precipitate wasstirred in boiling diethyl ether (300 ml), filtered off and dried,yielding 84.4 g (65.5%) of phenyl (4-methoxyphenyl)methyl!carbamate(interm. 2).

b) A mixture of 2,2-dimethoxyethylamine (41.5 ml) andN,N-dimethyl-4-pyridinamine (21.2 g) in triethylamine (96.7 ml) wasadded to a solution of intermediate 2 (84.4 g) in 1,4-dioxane (1000 ml).stirred at RT. The reaction mixture was stirred and refluxed overnight.The solvent was evaporated and the residue was taken up in CH₂ Cl₂ andwashed with 1N NaOH. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was taken up in CH₂Cl₂, washed three times with 1N HCl, washed with a 5% aqueous NaHCO₃solution, dried (MgSO₄), filtered, and the solvent was evaporated,yielding 82.3 g of N-(2,2-dimethoxyethyl)-N'-(4-methoxyphenyl)methyl!urea (interm. 3).

c) A solution of intermediate 3 (19 g) in methanol (572 ml) and water(143 ml) was cooled to 5° C. HCl (224 ml; o.5N) was added dropwise. Themixture was allowed to warm to RT. The reaction mixture was stirred for4 days at RT and filtered. NaOH (112 ml; 1N) was added slowly to thefiltrate, and the solvent was evaporated. The desired productprecipitated from the aqueous concentrate. CH₂ Cl₂ was added to dissolvethis compound. The organic layer was separated, washed with water, dried(MgSO₄), filtered and the solvent was evaporated. The solid residue wascrystallized from ethylacetate. The precipitate was filtered off, washedwith ethylacetate and diethyl ether, then dried, yielding 9.8 g (64%) of1,3-dihydro-1- (4-methoxyphenyl)methyl!-2H-imidazol-2-one (interm.4; mp.132.4° C.).

Using a similar procedure 1-(2,4-dimethoxyphenyl)methyl!-1,3-dihydro-2H-imidazol-2-one was prepared(interm. 5; mp. 160.8° C.).

EXAMPLE A.3

A mixture of (±)-N- 2- 3-(cyclopropylmethoxy)-4-methoxyphenyl!-2-(trimethylsilyl)-oxy!ethyl!-N-(dimethoxyethyl)urea (39.6 g) and HCl (150ml) in methanol (450 ml) was stirred for 48 hours at RT. The resultingmixture was concentrated and the concentrate (150 ml) was extractedthree times with CH₂ Cl₂. The combined organic layer were poured outinto a NaOH solution. The mixture was stirred and the layers wereseparated. The aqueous phase was extracted twice with CH₂ Cl₂. Theseparated organic layer was dried (MgSO₄), filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 95/5). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom ethylacetate/diisopropyl ether. The precipitate was filtered offand dried, yielding 10.36 g (37.9%) of 1- 2-3-(cyclopropylmethyloxy)-4-methoxyphenyl!-2-hydroxy-ethyl!-1,3-dihydro-2H-imidazol-2-one(interm. 6).

B. PREPARATION OF THE FINAL COMPOUNDS EXAMPLE B.1

a) Sodium bis(trimethylsilyl)amide (5 ml) was added to a solution of1,3-dihydro-2H-imidazol-2-one (0.84 g) in N,N-dimethylformamide (50 ml),stirred under a N₂ flow and cooled in an ice-bath. The reaction mixturewas stirred for 30 minutes. Intermediate 1 (2.69 g) was addedportionwise and the resulting reaction mixture was stirred for 16 hoursat RT, then for 2 hours at 50° C. The reaction mixture was stirred inmethyl isobutyl ketone (200 ml)/(50 ml) water. The solvent wasevaporated and methyl isobutyl ketone (100 ml) was added and azeotropedon the rotary evaporator. The mixture was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 97/3). Thedesired fractions were collected and the solvent was evaporated. Thewhite solid was stirred in diisopropyl ether, filtered off, washed withdiisopropyl ether and dried, yielding 0.4 g (12.6%) of 1- 2-3-(cyclopentyloxy)-4-methoxyphenyl!-2-oxoethyl!-1,3-dihydro-2H-imidazol-2-one(comp. 1; mp. 201.1° C.).

b) A suspension of compound 1 (3.6 g) in ethyl chloroformate (30 ml) wasstirred and refluxed for 1 hour. The solvent was evaporated and theresidue was redissolved in toluene. The solvent was evaporated again.The residue was purified by column chromatography over silica gel(eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 99/1). The pure fractions were collectedand the solvent was evaporated under reduced pressure. The residue wastreated with ethylacetate and the solvent was evaporated. The residue(1.1 g) was purified by HPLC over silica gel (eluent: CH₂ Cl₂ /CH₃ OH100/0 to 98/2). The pure fractions were collected and the solvent wasevaporated under reduced pressure. The residue (0.46 g) was taken up inethylacetate and the solvent was evaporated under reduced pressure. Theresidue was triturated in diisopropyl ether. The precipitate wasfiltered off, washed with diisopropyl ether and dried, yielding 0.4 g(10.3%) ethyl 3- 2-3-(cyclopentyloxy)-4-methoxphenyl!-2-oxoethyl!-2,3-dihydro-2-oxo-1H-imidazole-1-carboxylate(comp. 2; mp. 81.3° C.).

c) A mixture of compound 1 (3.16 g), hydroxylamine hydrochloride (0.84g) and potassium carbonate (1.82 g) in pyridine (20 ml) was stirred at80° C. for 3 hours. The reaction mixture was cooled and the solvent wasevaporated. The residue was taken up in water and extracted 3 times withCH₂ Cl₂. The separated organic layer was dried (MgSO₄), filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95/5). The purefractions were collected and the solvent was evaporated. The residue wascrystallized from CH₃ CN. The precipitate was filtered off and dried,yielding 1.4 g (42.3%) of 1- 2-3-(cyclopentyloxy)-4-methoxyphenyl!-2-(hydroxyimino)ethyl!-1,3-dihydro-2H-imidazolone(comp. 3; mp. 191.4° C.).

d) Sodium hydride (1.32 g) was added to dimethylsulfoxide (100 ml) at RTunder N₂ atmosphere. The reaction mixture was heated up to 60° C. andwas stirred for 1 hour. The reaction mixture was cooled to RT andmethyltriphenylphosphonium bromide (11.7 g) was added portionwise. Thereaction mixture was stirred for 30 minutes. Then compound 1 (3.16 g)was added portionwise. The reaction mixture was stirred for 1 hour,poured out into ice water and extracted three times with diethyl ether(150 ml). The separated organic layer was dried (MgSO₄), filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: ethylacetate/(CH₃ OH/NH₃)97.5/2.5). The pure fractions were collected and the solvent wasevaporated. The residue was triturated in diethyl ether. The precipitatewas filtered off, washed with diethyl ether, then dried, yielding 1 g(32%) of 1- 2-3-(cyclopentyloxy)-4-methoxy-phenyl!-2-propenyl!-1,3-dihydro-2H-imidazol-2-one(comp. 4; mp. 110.1° C.).

EXAMPLE B.2

a) 1-2-(3,4-dimethoxyphenyl)-2-oxoethyl!-1,3-dihydro-3-(phenylmethyl)-2H-imidazol-2-onewas prepared in a similar way as compound 1, but butyllithium (2.5M inhexane) was used instead of sodium bis(trimethylsilyl)amide (comp. 5;mp. 128.8° C.).

b) Phenyllithium (15 ml) was added to a solution of compound 5 (3.52 g)in THF (100 ml), stirred at -78° C. under a N₂ flow. The reactionmixture was stirred for another 2 hours at -78° C. The mixture wasallowed to warm to RT, while stirring for one hour. Water (50 ml) wascarefully added and the mixture was stirred for 20 minutes, thenextracted twice with CH₂ Cl₂ (100 ml). The separated organic layer wasdried (MgSO₄), filtered, and the solvent was evaporated. The residue wascrystallized from ethanol and the precipitate was filtered off, washedwith ethanol and diethyl ether, then dried, yielding 1.27 g of 1-2-(3,4-dimethoxy-phenyl)-2-oxoethyl!-1,3-dihydro-2H-imidazol-2-one(comp. 6).

EXAMPLE B.3

a) A mixture of ethyl 3-2-(3,4-dimethoxyphenyl)-2-oxoethyl!-2-oxo-1-imidazolidine-1-carboxylate(0.5 g),prepared according to the procedure described in example B.1.b,and potassium carbonate (14 g) in ethanol (100 ml) was stirred andrefluxed for 30 minutes. The reaction mixture was cooled, poured outinto water (200 ml) and the resulting mixture was extracted three timeswith CH₂ Cl₂. The combined organic layers were evaporated and theresidue was purified by column chromatography over silica gel (eluent:CH₂ Cl₂ /CH₃ OH 95/5). The pure fractions were collected and the solventwas evaporated. The residue was crystallized from CH₃ CN and theprecipitate was filtered off and dried, yielding 1.8 g (41.7%) of 1-2-(3,4-dimethoxyphenyl)-2-oxoethyl!-2-imidazolidinone (comp. 7; mp.166.6° C.).

b) A mixture of compound 7 (2.64 g), 2,3-dihydro-4H-pyran (0.84 g) andp-toluenesulfonic acid monohydrate (cat. quant.) in toluene (50 ml) wasstirred at RT for 1 hour. The reaction mixture was stirred and refluxedfor another hour. The solvent was evaporated and the residue waspurified by short column chromatography over silica gel (eluent: CH₂ Cl₂/CH₃ OH 98/2). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from ethylacetate and theprecipitate was filtered off, washed with ethylacetate and dried,yielding 0.2 g (6%) of (±)-1-2-(3,4-dimethoxyphenyl)-2-oxoethyl!-3-(tetrahydro-2H-pyran-2-yl)-2-imidazolidinone(comp. 8; mp. 119.7° C.).

c) A mixture of sodium hydride (8.64 g) in THF (700 ml) was stirred atRT under a N₂ flow. Diethyl cyanomethylphosphonate (31.86 g) was addeddropwise while keeping the temperature below 15° C. The reaction mixturewas stirred for 15 minutes. Compound 7 (15.84 g) was added portionwiseand stirring was continued for 2 hours. The reaction mixture was cooledon an ice-bath, decomposed with an aqueous NH₄ Cl solution and thismixture was extracted three times with CH₂ Cl₂. The separated organiclayer was dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:ethylacetate/C₂ H₅ OH 99/1). The desired fraction was collected and thesolvent was evaporated, the residue was stirred in diisopropyl ether.The precipitate was filtered off and dried, yielding 10.16 g (59%) of(E)-3-(3,4-dimethoxyphenyl)-4-(2-oxo-1-imidazolidinyl)-2-butenenitrile(comp. 9).

EXAMPLE B.4

Sodium hydride (0.2 g; 60%) was added to a cold (0° C.) solution ofdimethylformamide (30 ml). A solution of intermediate 4 (1.02 g) indimethyllformamide (20 ml) was added dropwise and the mixture wasstirred for 2 hours under N₂ flow. 2-Bromo-1-3-(cyclopentyloxy)-4-methoxyphenyl!ethanone (1.75 g) was addedportionwise and the resulting reaction mixture was stirred for 2 hours.The mixture was cooled to 0° C. A saturated aqueous NH₄ Cl solution (100ml) was added dropwise. This mixture was extracted twice with toluene(100 ml). The separated organic layer was dried (MgSO₄), filtered andthe solvent evaporated. The residue was purified by columnchromatography over silica gel (eluent: ethylacetate/(CH₃ OH/NH₃)97.5/2.5). The desired fractions were collected and the solvent wasevaporated. The residue was triturated in DIPE, filtered off, washedwith DIPE, then dried, yielding 0.4 g (16%) of 1- 2-3-(cyclopentyloxy)-4-methoxyphenyl!-2-oxoethyl!-1,3-dihydro-3-(4-methoxyphenyl)methyl!-2H-imidazol-2-one (comp. 10; mp. 105.5° C.).

EXAMPLE B.5

A mixture of oxalyl chloride (1.91 g) in CH₂ Cl₂ (30 ml) was stirred at-60° C. under N₂ flow. A mixture of dimethylsulfoxide (2.36 g) in CH₂Cl₂ (8 ml) was added dropwise at -60° C. The mixture was stirred at -60°C. for 5 minutes. A mixture of intermediate 6 (3.04 g) in CH₂ Cl₂ (50ml) was added at -60° C. The mixture was stirred at -60° C. for 15 min.Triethylamine (5.5 g) was added at -60° C. The mixture was stirred at-60° C. for 5 minutes, then allowed to warm to room temperature,decomposed with water (60 ml) and separated into its layers. The aqueouslayer was extracted three times with CH₂ Cl₂. The combined organic layerwas dried (MgSO₄), filtered and the solvent was evaporated. The residuewas purified by column chromatography over silica gel (eluent: CH₂ Cl₂/CH₃ OH 95/5). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from CH₃ CN, yielding 1.2 g(39.7%) of 1- 2-3-(cyclopropylmethyloxy)-4-methoxyphenyl!-2-oxoethyl!-1,3-dihydro-2H-imidazol-2-one(comp. 18).

The following compounds were prepared according to one of the aboveexamples (Ex. No.).

                                      TABLE 1    __________________________________________________________________________     ##STR21##    Comp        Ex    No  No R.sup.1                 X   AB      L         Physical data    __________________________________________________________________________     1  B.1.a           cyclopentyl                 O   CHCH    H         --     2  B.1.b           cyclopentyl                 O   CHCH    C(O)OC.sub.2 H.sub.5                                       mp.  81.3° C.     3  B.1.c           cyclopentyl                 NOH CHCH    H         mp. 191.4° C.     4  B.1.d           cyclopentyl                 CH.sub.2                     CHCH    H         mp. 110.1° C.     5  B.2.a           CH.sub.3                 O   CHCH    benzyl    mp. 128.8° C.     6  B.2.b           CH.sub.3                 O   CHCH    H         --     7  B.3.a           CH.sub.3                 O   CH.sub.2CH.sub.2                             H         mp. 166.6° C.     8  B.3.b           CH.sub.3                 O   CH.sub.2CH.sub.2                             2-tetrahydropyranyl                                       mp. 166.6° C.     9  B.3.c           CH.sub.3                 CHCN                     CH.sub.2CH.sub.2                             H         E isomer    10  B.4           cyclopentyl                 O   CHCH    4-methoxybenzyl                                       mp. 105.5° C.    11  B.1.a           CH.sub.3                 O   CHCH    diphenylmethyl                                       mp. 140.8° C.    12  B.1.a           CH.sub.3                 O   CHCH    2,4-dimethoxybenzyl                                       mp. 129.2° C.    13  B.3.a           cyclopentyl                 O   CH.sub.2CH.sub.2                             H         mp. 174.8° C.    14  B.1.a           cyclopentyl                 O   CH.sub.2CH.sub.2                             C(O)OC.sub.2 H.sub.5                                       mp.  97.4° C.    15  B.1.a           CH.sub.3                 O   CH.sub.2CH.sub.2                             C(O)OC.sub.2 H.sub.5                                       mp. 133.9° C.    16  B.1.a           CH.sub.3                 O   CHCH    C(O)OC.sub.2 H.sub.5                                       mp. 125.5° C.    17  B.1.c           CH.sub.3                 NOH CH.sub.2CH.sub.2                             H         mp. 171.2° C.    18  B.5           cyclopropyl-                 O   CHCH    H         --           methyl    __________________________________________________________________________

C. PHARMACOLOGICAL EXAMPLE EXAMPLE C.1 Inhibition of Recombinant HumanMononuclear Lymphocyte (MNL) Phosphodiesterase Type IV B Produced inInsect Cells with a Baculovirus Vector

The alleviating and/or curing effect of the instant compounds onallergic and atopic diseases was assessed by an in vitro assay system todetect an inhibiting effect on the recombinant human MNLphosphodiesterase type IV B.

Seventy-two hours after infection with recombinant baculovirus, theinsect cells were harvested and pelleted at 500 g for 5 minutes. Thecells were lysed in 10 ml lysis-buffer consisting of 20 mM Tris, 10 mMEGTA, 2 mM Na₂ EDTA, 1% Triton-X-100, 1 mM Na₃ VO₄, 10 mM NaF, 2 μg/mlof leupeptine, pepstatine and aprotinine, 0.3 μg/ml benzamidine and 100μg/ml TPCK pH 7.5. After 5 minutes on ice, solubilized cells werecentrifuged at 4000 rpm for 15 minutes at 4° C. The resultingsupernatant was filtered through a 0.45 μm filter (Millipore) andbrought to TBS buffer (50 mM Tris, 150 mM NaCl pH 7.4).

The supernatant containing phosphodiesterase (PDE) type IV B, wassubsequently loaded onto a 5 ml anti-FLAG-M₂ affinity gel column,previously activated with 5 ml 100 mM glycine pH 3.5 and equilibratedwith 20 ml 50 mM Tris, 150 mM NaCl pH 7.4. After washing the column withequilibration buffer, PDE IV was eluted in 1.5 ml fractions containing37.5 μl 1M Tris pH 8. The fractions were dialyzed overnight against 20mM Tris, 2mM Na₂ EDTA and 400 mM NaCl pH 7.5 and tested for PDE IVactivity. Indentification was done on SDS PAGE and Western Blot(anti-FLAG-M₂). Active fractions were pooled, brought to 10% glyceroland stored at -70° C.

The incubation mixture (pH 8) (200 μl) contained 20 mM Tris, 10 mMmagnesium sulphate, 0.8 μM ³ H-cAMP (310 mCi/mmole) and thephosphodiesterase type IV, the amount depending on the enzymaticactivity. A protein concentration was chosen that showed a linearincrease of phosphodiesterase activity during an incubation period ofmaximum 10 minutes at 37° C. and where less than 10% of the initialsubstrate was hydrolyzed.

When the effect of different compounds on phosphodiesterase activity wastested, the medium without cAMP was incubated with the compound(s) orits carrier (DMSO-1% final concentration) for 5 min. The enzymaticreaction was started by addition of ³ H-cAMP and stopped 10 min laterafter transferring the microtiter-plate in a waterbath at 100° C. for 5min. After cooling to room temperature, alkaline phosphatase (0.25μg/ml) was added and the mixture was incubated at 37° C. for 20 min. 100μl of the mixture was subsequently applied to a GF-Bfilter-microtiter-plate (Millipore) filled with 300 μl DEAE-Sephadex-A25suspension. The plate was washed 3 times with 75 μl 20 mM Tris pH 7.5and the filtrates were collected for counting in the Packard Top Countscintillation counter.

The inhibiting effect of the present compounds on recombinant human MNLphosphodiesterase PDE IV B was measured at different concentrations ofthe instant compounds. The IC₅₀ values (expressed in M) were calculatedgraphically from the thus obtained inhibition values. Compound Nos. 1and 4 had an IC₅₀ value lower than 1×10⁻⁶ M. The other compounds had anIC₅₀ value higher than or equal to 1×10⁻⁶ M.

EXAMPLE C.2 Dextran-Induced Oedema Formation in Mouse Ear

Systemic injection of dextran T500 in normal, non-sensitized miceelicits increased vascular permeability, leading to extravasation andoedema of the extremities. When dextran is injected together with a bluedye, blueing of the ears is the most prominent feature of oedematousresponse.

Male Swiss mice weighing 24-26 g were orally pretreated with the testcompound dissolved in PEG-200 at different concentrations or solvent.One hour later, the mice were given an intravenous injection with anisotonic saline solution containing 12 mg/ml dextran T500 and 2.6 mg/mlpontamine sky-blue dye, in a volume of 0.1 ml per 10 g body weight. Onehour and forty-five minutes later, the animals are sacrificed by etherand their ears removed. Extraction and quantification of theextravasated dye is done as described by Van Wauwe and Goossens (DrugDev. Res. 1986, 8, 213-218).

The extravasation of the dye is characterized by the blueing value whichis defined as the concentration of the extracted dye in both ears. Thebackground blueing value was determined once as the mean blueing valueobtained by injecting a group of mice with a saline solution containingonly dextran T500 and the blue dye. Table 2 lists the percentageinhibition of the extravasation of the dye when compared with thebackground extravasation of the dye when the test compound wasadministered at a dose of 5 mg/kg.

                  TABLE 2    ______________________________________    Comp. No.     % inhibition    ______________________________________    1             48.3    2             55.6    5             28.7    7             22.6    8             5.2    9             53.8    10            56.0    11            34.6    12            26.4    13            27.9    15            19.2    ______________________________________

D. COMPOSITION EXAMPLES

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic or topical administration to animal and humansubjects in accordance with the present invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable addition saltthereof.

EXAMPLE D.1 Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wetpowder mixture was sieved, dried and sieved again. Then there was added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole was mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere was added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there were added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten anddissolved in 75 ml of dichloromethane. The latter solution was added tothe former and then there were added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concentrated color suspension andthe whole was homogenated. The tablet cores were coated with the thusobtained mixture in a coating apparatus.

EXAMPLE D.2 2% Cream

75 mg stearyl alcohol, 2 mg cetyl alcohol, 20 mg sorbitan monostearateand 10 mg isopropyl myristate are introduced into a doublewall jacketedvessel and heated until the mixture has completely molten. This mixtureis added to a separately prepared mixture of purified water, 200 mgpropylene glycol and 15 mg polysorbate 60 having a temperature of 70° to75° C. while using a homogenizer for liquids. The resulting emulsion isallowed to cool to below 25° C. while continuously mixing. A solution of20 mg A.I., 1 mg polysorbate 80 and purified water and a solution of 2mg sodium sulfite anhydrous in purified water are next added to theemulsion while continuously mixing. The cream, 1 g of the A.I. ishomogenized and filled into suitable tubes.

EXAMPLE D.3 2% Topical Gel

To a solution of 200 mg hydroxypropyl β-cyclodextrine in purified wateris added 20 mg of A.I. while stirring. Hydrochloric acid is added untilcomplete dissolution and then sodium hydroxide is added until pH 6.0.This solution is added to a dispersion of 10 mg carrageenan PJ in 50 mgpropylene glylcol while mixing. While mixing slowly, the mixture isheated to 50° C. and allowed to cool to about 35° C. whereupon 50 mgethyl alcohol 95% (v/v) is added. The rest of the purified water q.s. ad1 g is added and the mixture is mixed to homogenous.

EXAMPLE D.4 2% Topical Cream

To a solution of 200 mg hydroxypropyl β-cyclodextrine in purified wateris added 20 mg of A.I. while stirring. Hydrochloric acid is added untilcomplete dissolution and next sodium hydroxide is added until pH 6.0.While stirring, 50 mg glycerol and 35 mg polysorbate 60 are added andthe mixture is heated to 70° C. The resulting mixture is added to amixture of 100 mg mineral oil, 20 mg stearyl alcohol, 20 mg cetylalcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 having atemperature of 70° C. while mixing slowly. After cooling down to below25° C., the rest of the purified water q.s. ad 1 g is added and themixture is mixed to homogenous.

EXAMPLE D.5 2% Liposome Formulation

A mixture of 10 g phosphatidyl choline and 1 g cholesterol in 7.5 gethyl alcohol is stirred and heated at 40° C. until completedissolution. 2 g A.I. microfine is dissolved in purified water by mixingwhile heating at 40° C. The alcoholic solution is added slowly to theaqueous solution while homogenizing during 10 minutes. 1.5 gHydroxypropyl-methylcellulose in purified water is added while mixinguntil swelling is complete. The resulting solution is adjusted to pH 5.0with sodium hydroxide 1N and diluted with the rest of the purified waterad 100 g.

We claim:
 1. A compound of formula ##STR22## a N-oxide form, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof, wherein:R¹ and R² each independently are hydrogen; C₁₋₆ alkyl; difluoromethyl; trifluoromethyl; C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo 2.2.1!-2-heptenyl; bicyclo 2.2.1!heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; R³ is hydrogen, halo or C₁₋₆ alkyloxy; ##STR23## is a bivalent radical of formula ##STR24## wherein: R⁴ is hydrogen; cyano: C₁₋₆ alkyl; C₁₋₄ alkyloxycarbonyl; C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;R⁵ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, aminocarbonyl, mono- or di(C₁₋₄ alkyl)amino, mono- or di(C₁₋₄ alkyl)arninocarbonyl, Het¹ or aryl; n is 1, 2, 3, 4 or 5; Alk is C₁₋₄ alkanediyl; --A--B-- is a bivalent radical of formula: ##STR25## wherein each R⁶ and R⁷ independently is hydrogen or C₁₋₄ alkyl; L is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆ alkyloxycarbonyl; C₁₋₆ alkyl substituted with one or two substituents selected from the group consisting of hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, mono- and di(C₁₋₄ alkyl)amino, aryl and Het² ; C₃₋₆ alkenyl; C₃₋₆ alkenyl substituted with aryl; piperidinyl; piperidinyl substituted with C₁₋₄ alkyl or arylC₁₋₄ alkyl; C₁₋₆ alkylsulfonyl or arylsulfonyl; aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl, trifluoromethyl, amino, nitro, carboxyl, C₁₋₄ alkyloxycarbonyl and C₁₋₄ alkylcarbonylamino; Het¹ is pyridinyl; pyridinyl substituted with C₁₋₄ alkyl; furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl; thienyl substituted with C₁₋₄ alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substituted with C₁₋₄ alkyl or C₁₋₄ alkoxyC₁₋₄ alkyl; imidazolyl; imidazolyl substituted with C₁₋₄ alkyl; thiazolyl; thiazolyl substituted with C₁₋₄ alkyl; oxazolyl; oxazolyl substituted with C₁₋₄ alkyl; isoquinolinyl; isoquinolinyl substituted with C₁₋₄ alkyl; quinolinonyl, quinolinonyl substituted with C₁₋₄ alkyl; morpholinyl; piperidinyl; piperidinyl substituted with C₁₋₄ alkyl, C₁₋₄ alkyloxycarbonyl or arkylC₁₋₄ alkyl; piperazinyl; piperazinyl substituted with C₁₋₄ alkyl, C₁₋₄ alkyloxycarbonyl or arylC₁₋₄ alkyl; and Het² is morpholinyl; piperidinyl; piperidinyl substituted with C₁₋₄ alkyl or arkylC₁₋₄ alkyl; piperazinyl; piperazinyl substituted with C₁₋₄ alkyl or arkylC₁₋₄ alkyl; pyridinyl; pyridinyl substituted with C₁₋₄ alkyl; furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl or thienyl substituted with C₁₋₄ alkyl or C₁₋₄ alkylcarbonylamino.
 2. A compound according to claim 1 wherein:R¹ and R² each independently are hydrogen, C₁₋₆ alkyl, difluoromethyl, trifluoromethyl, C₃₋₆ cycloalkyl or bicyclo 2.2.1!-2-heptenyl; ##STR26## is a bivalent radical of formula ##STR27## wherein: R⁴ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino, Het¹ or aryl;R⁵ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, aminocarbonyl, mono- or di(C₁₋₄ alkyl)amino, mono- or di(C₁₋₄ alkyl)aminocarbonyl, Het¹ or aryl; n is 1, 2, 3, 4 or 5; L is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, mono- or di(C₁₋₄ alkyl)amino, aryl or Het² ; C₃₋₆ alkenyl; C₃₋₆ alkenyl substituted with aryl; piperidinyl; piperidinyl substituted with C₁₋₄ alkyl or arylC₁₋₄ alkyl; C₁₋₆ alkylsulfonyl or arylsulfonyl; aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl, trifluoromethyl, amino and C₁₋₄ alkylcarbonylamino.
 3. A compound according to claim 1 wherein ##STR28## is a radical of formula (a-2), (a-3) or (a-4).
 4. A compound according to claim 1 wherein R¹ is hydrogen; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; bicyclo 2.2.1!-2-heptenyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituents each independently selected from pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen.
 5. A compound according to claim 1 wherein R² is hydrogen, C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo 2.2.1!-2-heptenyl; bicyclo 2.2.1 !heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen.
 6. A compound according to claim 1 or 2 wherein R¹ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl and R² is C₁₋₆ alkyl.
 7. A compound according to any one of claims 1 to 6 wherein R³ is hydrogen.
 8. A compound according to any one of claims 1 to 7 wherein Alk is methylene or 1,2-ethanediyl.
 9. A compound according to any one of claims 1 to 8 wherein L is hydrogen or C₁₋₆ alkyl.
 10. A compound according to any one of claims 1 to 9 wherein --A--B-- is a bivalent radical of formula (b-1) wherein R⁶ and R⁷ both are hydrogen.
 11. A compound according to claim 1 wherein the compound is 1- 2- 3-(cyclopentyloxy)-4-methoxyphenyl!-2-oxoethyl!-1,3-dihydro-2H-imidazol-2-one or 1- 2- 3-(cyclopentyloxy)-4-methoxy-phenyl!-2-propenyl!-1,3-dihydro-2H-imidazol-2-one.
 12. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in any one of claims 1 to
 11. 13. A method of treating asthmatic or atopic diseases in a human in need of such treatment which comprises administering an effective amount of a compound as claimed in any one of claims 1 to
 11. 14. A method of treating atopic dermatitis in a human in need of such treatment which comprises administering an effective amount of a compound as claimed in any one of claims 1 to
 11. 